Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Abstract

There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

“…6). NDMC displays strong partial agonist activity at M 1 receptors (Davies et al 2005;Lameh et al 2007;Natesan et al 2007), and while CLZ has traditionally been considered to be a muscarinic antagonist, more recent work has shown that CLZ is a partial agonist at M 1 , M 2 , and M 3 receptors and is a full agonist at M 4 receptors (see Raedler et al 2007). Thus, CLZ and NDMC also appear to share similarities in terms of their activity at muscarinic receptors (which may or may not be related to their discriminative cue properties).…”

“…Recently, there has been increasing interest in the possibility that NDMC may be a novel APD because of its interesting in vitro receptor binding profile. Like CLZ, it is a potent 5-HT 2A antagonist, yet in contrast to CLZ, it is a partial agonist at DA D 2 (Lameh et al 2007;Natesan et al 2007) and at DA D 3 receptors (Burstein et al 2005;Novi et al 2007). It has been suggested that NDMC's unique muscarinic agonist properties may provide one molecular explanation for the superior clinical effects of CLZ (Weiner et al 2004) and may more effectively treat the cognitive deficits that are observed in schizophrenic patients (Li et al 2005).…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…At the doses chosen in my experiment (1.3 mg/kg for risperidone, 15 mg/kg for clozapine and 0.05 mg/kg for haloperidol), this level of dopamine D2 receptor occupancy would appear to have been achieved Natesan et al 2007;Wadenberg et al 2001b). Higher rates of D2 receptor occupancy are associated with extra-pyramidal side-effects (Natesan et al 2007;2008;Natesan et al 2006a;Wadenberg et al 2001b). Here I showed that these doses of APDs disrupted avoidance response without inducing any significant increase in escape failures.…”

“…Although sensitization to risperidone in a CAR paradigm has also been reported in adult rats (Gao and Li 2013) (Natesan et al 2007). This suggests that no significant increase in behavioural sensitivity to haloperidol was induced at any ages after drug washout.…”

“…Rats were weighed daily approximately 30 min before drug administration. Approximately 60-80% D2 receptor occupancy is required in order to acutely impair CAR behaviour (Natesan et al 2007;Wadenberg et al 2001b). …”